Idiopathic dilated cardiomyopathy (IDCM) is a leading cause of congestive heart failure, produces death and disability via heart failure and sudden cardiac death, and accounts for ~50% of heart transplants performed. As such this disorder is a lead candidate for cell-based therapy. The primary phenotype of dilated cardiomyopathy is an enlarged, remodeled ventricle with increases in end-diastolic and end-systolic volumes, reduced ejection fraction, and impaired contractile and diastolic function. Cell-based therapy holds great promise as a new approach to produce durable and sustainable improvements in dysfunctional hearts and to cause reverse remodeling. If these effects can be clinically established and optimized, there is enormous potential for improving clinical outcomes for the many patients suffering from dilated cardiomyopathy. Our group has extensive experience with catheter delivery of bone-marrow derived mesenchymal stem cells in patients with ischemic cardiomyopathy and is now poised to test this exciting clinical hypothesis in patients with non-ischemic cardiomyopathy. There is substantial scientific and public interest for cardiac regenerative cell therapy strategies, based on pre-clinical, translational, and early clinical studies. This trial is currently approved by the FDA under investigator initiated IND number BB-14419 (PI: Hare), and is therefore ready to be initiated. The specific aims of this proposal are: 1. To establish the safety and efficacy of bone marrow derived mesenchymal stem cell (MSC) therapy for patients with idiopathic dilated cardiomyopathy. We will perform a randomized comparison of autologous and allogeneic MSC therapy employing percutaneous delivery with a transendocardial catheter delivery system. 2. To compare two different bone marrow preparations - allogeneic vs. autologous bone marrow derived mesenchymal stem cells (MSCs) - for safety and efficacy in patients with non-ischemic cardiomyopathy. The mechanism of action at a phenotypic level will be assessed using cardiac magnetic resonance imaging (MRI) to measure MI size, regional and global LV function, tissue fibrosis, and tissue perfusion. A post-hoc analysis will be performed to test the hypothesis that in vitro assessments of cell morphology, cell surface markers, and cell colony growth potential may predict the ability of an individual patient's cells to improve the cardiac measures. 3. To assess cellular mechanisms of action of MSC therapy by measuring the capacity for endogenous cardiac stem cell proliferation and differentiation. Endomyocardial biopsies will be obtained from the patients enrolled in this trial and tested for their capacity to yield endogenous cardiac stem cells. PUBLIC HEALTH RELEVANCE: This clinical study will address a significant clinical need, namely the investigation of new and promising therapies for heart failure, one of the leading causes of cardiovascular death and disability. The proposed studies will elucidate new mechanisms of repair and regeneration of heart tissue.